Agent for improving cerebral metabolism including glucose ester derivatives

ABSTRACT

An agent for improvement of cerebral metabolism, containing as active ingredient a glucose ester derivative presented by the formula: ##STR1## and wherein the anomeric substitute in the formula is either α or β; R to R 4 , each represents H atom, a straight or branched acyl or a ring containing acyl having 2 to 8 carbon atoms, provided that at least one of said R to R 4  is the acyl group. 
     The present agent is effective for the treatment of cerebral disorders resulting from hypoglycemic shock, the reduced capacity of active glucose trasport through the blood-brain barrier, and senile dementia or senile movement functional disorders.

TECHNOLOGICAL ASPECT

This invention provides an agent for improving cerebral metabolism,including glucose ester derivatives (glucose pyranose derivatives),which is excellent in penetrating activity across the blood-brainbarrier.

BACKGROUND

Transport from blood to the cerebral tissue of substances necessary forthe maintenance of cerebral function is extremely impeded by theblood-brain barrier. Glucose, which is a sole and very important energysource for the cerebral tissue, is therefore, no exception as reportedby Goldstein (Scientific America., 254:74-83, 1986). The supply ofglucose from blood to inside of brain is controlled by carrier proteinswhich are specific for the blood-brain barrier, through their selectiveand active transport from the outside of the barrier to the cerebraltissue. Glucose transported to the cerebral tissue, is metabolized byhexokinase to glucose-6-phosphate, which is a very importantintermediate in glucose catabolism system, and then entered into ametabolic pathway where it is degraded up to an end product of theenergy generating system while generating simultaneously with highenergy-phosphoric compounds such as ATP through its linkedphosphorylation reaction under influence of oxidation, decarboxylationand other reactions.

Approximately 20% of the total oxygen consumption in the body takesplace in the brain where a large amount of glucose is concomitantlyconsumed. In the cerebral tissue, however, there is no sugar storage inthe form of glycogen, and therefore, the brain is liable to fall into astate of energy metabolism dysfunction within a short time when glucosesupply is disturbed due to blood hypoglycemia or to a decrease in thecapacity of the blood-brain barrier transport, the conditions of whichare just similar to those of respiratory or circulation disorders.

In an acute situation, disorders appear first in an metabolically activetissue site with the highest sugar consumption, then to the next site inan order of sugar consumption degrees. A cerebrum dysfunction starts ata blood sugar level lower than 60 mg/dl, and hypoglycemic coma may becaused when its level becomes lower than 20 mg/dl. In this case, 50% ofhuman subjects will die unless they get an improvement in the cerebralenergy metabolic disorder within 5 minutes. Even if survived, they maysuffer from sequela such as dementia and a vegetable state depend on thedegree of disorder. Similar to brain hypoxia, an irreversible neuronalsymptom is known to progress in some cases even afer revival from comaas a result of regressive degeneration due to delayed cell deathfollowing excess release of glutamic acid and elicitation of a calciumconcentration increase in neuronal cells, particularly when the comastate prolonged or spasm occurred repeatedly.

The current treatment that has been considered best for cerebraldisorders resulting from hypoglycemic shock and disturbance inconsciousness associated with diabetic hypoglycemia is oral orintravenous administration of glucose. This therapy method has beenwidely exercised. This treatment can raise a blood sugar levelimmediately. However, since glucose per se cannot cross the barrier,glucose needs to be captured first by carrier proteins and thensubjected to an active and selective transport together with its carrierthrough the blood-brain barrier into cerebral tissues. Because of thisfact, a time-lag of a few minutes is inevitable between administrationof glucose and attainment of a sufficient concentration of glucose at asite of the cerebral tissue. This detriment in glucose administrationhas remained to be solved, since supply of energy source at a sufficientlevel to the cerebral tissue of these patients must be carried out asurgently as possible.

In the same token as above, a decreased capacity in the active transportof glucose at the blood-brain barrier due to aging or cerebral disorderscan result in reducing cerebral metabolic functional competence andcausing necrosis of the cerebral tissue. Thereby, the administration ofglucose, as mentioned above, to the patients with incompetence in activetransport of glucose through the blood-brain barrier would result inonly an increase in blood sugar levels, but hardly in providing theircerebral tissue with energy source. Thus, this therapy cannot be anefficient one for improvement or maintenance of cerebral metabolism inthese patients.

In ventors of this invention studied this problem with use of 1, 3, 4,6-tetra-O-acetyl-N-(m-iodobenzoyl)-glucosamine and 1, 3, 4,6-tetra-O-pivaloyl-N-(m-iodobenzoyl)-glucosamine, and reported a hightransport rate of glucosamine ester derivatives across the blood-brainbarrier in Journal of Labelled Compounds and Radiopharmaceuticals,30:300-303, 1991. However, anticipated has been the appearance ofglucose derivatives such as those that have a high transport rate at theblood-brain barrier, regardless of the active transport regulatorycondition, and can reach the cerebral tissues quickly so as to beconverted to glucose-6-phosphate, therefore act very effectively inimprovement of the cerebral metabolism in the patients who sufferedblood hypoglycemic shock or diabetic hypoglycemic coma. Thus, thisinvention is intended to explore this type of contemplation.

DISCLOSURE OF THE INVENTION

These inventors gave rise to the discoveries described below, leading tothe invention presented herein. The discoveries are as follws: 1)glucose ester derivatives, having a transport mechanism different fromthat for glucose, can reach the cerebral tissue after crossing theblood-brain barrier without any substantial time lag that often occursin case of glucose transport; 2) in the cerebral tissues, glucose esterderivatives can be converted to the aforementioned catabolicintermediate metabolite, glucose-6-phosphate, at much more acceleratedrate than the catabolic rate of these derivatives present in somatictissues outside the blood-brain barrier. These findings led us to thisinvention described herein. That is, in this invention, a glucose esterderivative of the formula below. ##STR2## The anormeric substitute inthe formula is either α or β; R-R₄, are identical or different eachother, and each represents H atom, a straight or branched acyl grouphaving 2 to 8 carbons, or acyl group containing a ring structure, and inaddition, at least 1 of said R-R₄ is the acyl group is used as an activeingredient of the present cerebral metabolism improving agent.!

THE BEST MODES FOR THE PRACTICE OF THE INVENTION

Any of the glucose ester derivatives, shown as the general formulaabove, can be converted quickly into glucose-6-phosphate followingadministration, Because of this characteristic, these derivatives aremost effective in improvement of cerebral metabolism in such patientswho suffered from blood hypoglycemic shock, and diabetic hypoglycemiccoma that require urgently the supply of glucose energy source, and alsoin the patients who suffer from dementia or motor function disorderresulted from lack of glucose energy source due to the transportdisfunction at the blood-brain barrier.

The most preferable glucose ester derivatives in this invention are asfollows: 1, 3, 4, 6,-tetra-O-acetyl-D-glucose; 1, 2, 3, 4,6,-penta-O-acetyl-D-glucose; 1, 2-di-O-acetyl-3, 4,6-tri-O-(2-methylbutyryl)-D-glucose; 1,3,-di-O-acetyl-6-O-butyryl-D-glucose; 1, 3,4,-tri-O-acetyl-6-O-nicotinoyl-D-glucose; 1, 2-di-O-benzoyl-D-glucose;1-O-cinnamoyl-D-glucose, etc. In particular, 1, 2-di-O-acetyl-D-glucose,3, 4, 6-tri-O-acetyl-D-glucose, 1, 3, 4, 6-tetra-O-acetyl-D-glucose, 1,2, 3, 4, 6-penta-O-acetyl-D-glucose are very effective and preferred.

Glucose ester derivatives of this invention can be administered orallyor non-orally in formulas of tablets, capsules, granules, syrup, troche,elixir, injection, and suspension that are manufactured in generalpharmacological preparation methods with use of fillers, disintegrant,binders, lubricants, sweetening agents, alcohol, solubilizer, bufferingagents, water-soluble bases, emulsifying agents, suspending agents.

The effects of the invention shall be minutely stated in connection withthe following Reference Examples and Examples, and however, these shouldnot be taken as being limitative to the present invention and theworking effects thereof.

REFERENCE EXAMPLE 1!

The compound, 1, 3, 4, 6-tetra-O-acetyl-2-¹⁸ F-D-glucose (¹⁸ F-AFDE)labelled with an electrophilic reagent, ¹⁸ F, was prepared according tothe method of Shiue et al (Journal of Nuclear Medicine, 23:889-903,1982); ¹⁸ F acetate, obtained by passing 18.2 mg ¹⁸ F through a columnfilled with sodium acetate, was subjected to the reaction at 0° C. with3, 4, 6-tri-O-acetyl-glucal in solvent of freon-11, resulting in a yieldof 60 mg ¹⁸ F-AFDG.

REFERENCE EXAMPLE 2!

The control compound, 2-¹⁸ F-D-glucose (¹⁸ F-FDG) was obtained in anamount of 10 mg by addition of 5 ml of 1N solution of hydrochloric acidto 30 mg of ¹⁸ F-AFDG of the above Reference Example 1 followed byheating the mixture at 130° C. for 15 minutes.

EXAMPLE 1!

Normal male mice of the ddy strain at 6 weeks of age were injectedintravenously through tail vein with 0.05 ml of mM ¹⁸ F in DMSOsolution. Measurement of its blood concentrations and radioactivities inthe cerebral tissue of the mice revealed that the radioactivity could bedetected in the cerebral tissue immediately after administration, andlevels of the radioactivity increased up to 30 minutes, whereas theblood radioactivity levels decreased consistently followingadministration, and at 10 minutes of administration, and thereafter theradioactivity was found to be higher in the cerebral tissue than in theblood (FIG. 1).

EXAMPLE 2!

Two tenth ml of ¹⁸ F-FDG or ¹⁸ F-AFDG in 50% DMSO solution was injectedinto the carotid artery of three different groups of rats: the firstgroup of rats injected without addition of glucose; the second groupwith 20 mM glucose; the third group with 80 mM glucose, and then theradioactivity of the respective labelled compound transported into thecerebral tissue was measured. The transport rate of ¹⁸ F-FDG to thecerebral tissue was decreased inversely as the concentration of glucosewas increased. On the other hand, ¹⁸ F-FDG , an ester derivative, couldreach the cerebral tissue at transport rates higher than 90% with nocompetition even to the maximum concentration of glucose, 80 mM (FIG.2). The finding that the transport of the glucose ester derivative tothe cerebral tissue was not influenced by varying concentratioins ofglucose indicates that there is a transport mechanism across theblood-brain barrier for the glucose ester derivative different from themechanism for glucose transport.

EXAMPLE 3!

Mice were given an intravenous injection of 0.05 ml solution of 0.5 mM¹⁸ F-AFD in DMSO. The cerebral tissue harvested at 0.5, 2, 5, 60 and 180minutes were homogenized for one minute in ethanol, and then centrifugedat 700×g for 10 minutes. The supernatant was collected for individualmeasurements of ¹⁸ F-AFDG, its intra-cerebral metabolites, ¹⁸ F-FD and¹⁸ F-FDG-6-phosphate.

It was noted that approximately 40% ¹⁸ F-AFDG of reached the cerebraltissue, and also its intra-cerebral metaboletes, ¹⁸ F-FD and ¹⁸F-FDG-6-phosphate emerged within 0.5 minute following administration.Thereafter, ¹⁸ F-AFDG was metabolized into ¹⁸ F-FDG-6-phosphate, and theconcentration of the latter was raised markedly (FIG. 3).

When intra-cerebral concentrations of metabolites were compared withthose in the blood at 5, 60 and 180 minutes following administration of¹⁸ F-AFDG, ¹⁸ F-FDG-6-phosphate was found at the highest proportion inthe cerebral tissue at the respective time points of measurement, and at180 minutes the entire ¹⁸ F-AFDG was found to be metabolized into ¹⁸F-FDG-6-phosphate, demonstrating a very rapid metabolic rate of theglucose ester derivative to glucose-6-phosphate, especially in thecerebral tissue (FIGS. 4 and 5).

In FIGS. 4 and 5, peaks at 0, 0.25, and 0.75 on axis represent peaks of¹⁸ F-FDG-6-phosphate, ¹⁸ F-FDG and ¹⁸ F-AFDG, respectively, where thehighest peak measured is designated 100%, and other two peaks areexpressed as relative ratios of the highest.

LEGEND OF DRAWINGS FIG. 1!

Kinetic changes in radioactivities in the blood and the cerebral tissueof the mice injected with ¹⁸ F-AFDG.

FIG. 2!

Transport rates to the cerebral tissue of ¹⁸ F-AFDG and ¹⁸ F-FDGadministered to rats with varying concentrations of glucose.

FIG. 3!

Kinetic changes of ¹⁸ F-AFDG, and its metabolites in the cerebral tissueof the mice administered with this labelled compound.

FIG. 4!

Kinetic changes in the ratio of intra-cerebral concentrations of ¹⁸F-AFDG and its metabolites in the mice administered this labelledcompound.

FIG. 5!

Kinetic changes in the ratio of blood concentrations of ¹⁸ F-AFDG andits metabolites in mice administered this labelled compound.

We claim:
 1. A method for the treatment of cerebral functional disordersresulting from a reduced capacity for active glucose transport through ablood-brain barrier in a patient, which comprises administering to saidpatient an effective amount of an agent containing as an effectivecomponent a glucose ester derivative represented by the formula:##STR3## in which the anomeric form is either α or β; each of R-R₄ isselected from the group consisting of H atom, a straight or branchedacyl group having 2 to 8 carbon atoms, and a ring containing acyl group,provided that at least one of the said R-R₄ is the acyl group and apharmaceutically acceptable carrier.
 2. The method according to claim 1,wherein said effective component is selected from the group consistingof 1,3,4,6-tetra-O-acetyl-D-glucose; 1,2,3,4,6-penta-O-acetyl-D-glucose;1,2-di-O-acetyl-3,4,6-tri-O-(2-methylbutyryl)-D-glucose;1,3,-di-O-acetyl-6-O-butyryl-D-glucose;1,3,4-tri-O-acetyl-6-O-nicotinoyl-D-glucose; 1,2-di-O-benzoyl-D-glucose;1-O-cinnamoyl-D-glucose; 1,2-di-O-acetyl-D-glucose and3,4,6-tri-O-acetyl-D-glucose.
 3. The method according to claim 2,wherein the effective component is 1,3,4,6-tetra-O-acetyl-D-glucose.